Method for the treatment or prevention of Flavivirus infections using nucleoside analogues

ABSTRACT

The present invention relates to a method for the treatment or prevention of Flavivirus infections using nucleoside analogues in a host comprising administering a therapeutically effective amount of a compound having the formula I or a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

[0001] The present invention relates to a method for the treatment orprevention of Flavivirus infections using nucleoside analogues.

BACKGROUND OF THE INVENTION

[0002] Hepatitis is a disease occurring throughout the world. It isgenerally of viral nature, although there are other causes known. Viralhepatitis is by far the most common form of hepatitis. Nearly 750,000Americans are affected by hepatitis each year, and out of those, morethan 150,000 are infected with the hepatitis C virus (HCV).

[0003] HCV is a positive-stranded RNA virus belonging to theFlaviviridae family and has closest relationship to the pestivirusesthat include hog cholera virus and bovine viral diarrhea virus (BVDV).HCV is believed to replicate through the production of a complementarynegative-strand RNA template. Due to the lack of an efficient culturereplication system for the virus, HCV particles were isolated frompooled human plasma and shown, by electron microscopy, to have adiameter of about 50-60 nm. The HCV genome is a single-stranded,positive-sense RNA of about 9,600 bp coding for a polyprotein of3009-3030 amino-acids, which is cleaved co- and pqst-translationally bycellular and two viral proteinases into mature viral proteins (core, E1,E2, p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). It isbelieved that thestructural proteins, E1 and E2, the major glycoproteins are embeddedinto a viral lipid envelop and form stable heterodimers. It is alsobelieved that the structural core protein interacts with the viral RNAgenome to form the nucleocapsid. The nonstructural proteins designatedNS2 to NS5 include proteins with enzymatic functions involved in virusreplication and protein processing including a polymerase, protease andhelicase.

[0004] The main source of contamination with HCV is blood. The magnitudeof the HCV infection as a health problem is illustrated by theprevalence among high-risk groups. For example, 60% to 90% ofhemophiliacs and more than 80% of intravenous drug abusers in westerncountries are chronically infected with HCV. For intravenous drugabusers, the prevalence varies from about 28% to 70% depending on thepopulation studied. The proportion of new HCV infections associated withpost-transfusion has been markedly reduced lately due to advances indiagnostic tools used to screen blood donors.

[0005] The only treatment currently available for HCV infection isinterferon-α (IFN-α). However, according to different clinical studies,only 70% of treated patients normalize alanine aminotransferase (ALT)levels in the serum and after discontinuation of IFN, 35% to 45% ofthese responders relapse. In general, only 20% to 25% of patients havelong-term responses to IFN. Clinical studies have shown that combinationtreatment with IFN and ribavirin (RIBA) results in a superior clinicalresponse than IFN alone. Different genotypes of HCV respond differentlyto IFN therapy, genotype 1b is more resistant to IFN therapy than type 2and 3.

[0006] There is therefore a great need for the further development ofanti-viral agents.

SUMMARY OF THE INVENTION

[0007] The present invention relates to a method for the treatment orprevention of Flavivirus infections in a host comprising administering atherapeutically effective amount of a compound having the formula I or apharmaceutically acceptable salt thereof:

[0008] wherein

[0009] B is chosen from a purine, a pyrimidine or an analogue thereof;

[0010] Ra is chosen from H, monophosphate, diphosphate, triphosphate,carbonyl substituted with a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, and

[0011]  wherein each Rc are independently chosen from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl and an hydroxy protecting group;and

[0012] Z is halogen or. ORbi wherein Rb is choseh from of H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ acyl, or an hydroxy protecting group

[0013] D₁ and D₂ are independently selected from. N₃, F, or H, and D₂can also be joined to be chosen from C₃-cycloalkyl, -═CH₂, or -═CF₂, and

[0014] wherein said compound is in the form of a single enantiomer or amixture thereof including racemic mixtures;

[0015] with the proviso that when B is adenine, Z is ORb, D₁ is H, D₂ isH and Rb is H, Ra is not triphosphate or H.

[0016] In another aspect, there is provided a pharmaceutical formulationcomprising the compounds of the invention in combination with apharmaceutically acceptable carrier or excipient.

[0017] Still another aspect, there is provided a method for treating orpreventing a viral infection in a host comprising administering acombination comprising at least one compound according to formula I andat least one further therapeutic agent.

[0018] In another aspect of the invention is the use of a compoundaccording to formula I, for the preparation of a medicament for treatingor preventing a viral infections in a host.

DETAILED DESCRIPTION OF THE INVENTION

[0019] In one embodiment, the viral infection is chosen from Flavivirusinfections.

[0020] In one embodiment, the Flavivirus infection is chosen fromHepatitis C virus (HCV), bovine viral diarrhea virus (BVDV), hog choleravirus and yellow fever virus.

[0021] In an other embodiment, the Flavivirus infection is Hepatitis Cvirus.

[0022] In one embodiment, there is also provided a method for inhibitingor reducing the activity of viral polymerase in a host comprisingadministering a therapeutically effective amount of a compound havingthe formula I.

[0023] In another embodiment, the viral polymerase is HCV polymerase.

[0024] The present invention relates to a method for the treatment orprevention of Flavivirus infections using nucleoside analogues in a hostcomprising administering a therapeutically effective amount of acompound having the formula Ia or a pharmaceutically acceptable saltthereof:

[0025] wherein

[0026] B is chosen from a purine, a pyrimidine or an analogue thereof;

[0027] Ra is chosen from H, monophosphate, diphosphate, triphosphate,carbonyl substituted with a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, and —

[0028]  wherein each Rc are independently chosen from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl and an hydroxy protecting group;and

[0029] Z is halogen or ORb, wherein Rb is chosen from of H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ acyl, or an hydroxy protecting group;and

[0030] wherein said compound is in the formof a single enantiomer or amixture thereof including racemic mixtures;

[0031] with the proviso that when B is adenine, Z is ORb and Rb is 10H,Ra is not triphosphate or H.

[0032] In one embodiment, the compounds and methods of the presentinvention comprise those wherein the following embodiments are present,either independently or in combination.

[0033] In one embodiment, B is chosen from adenin-9-yl, guanin-9-yl,inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl,2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl, uracil-1-yl,3-carboxamido-1,2,4-triazol-1-yl, 1-deaza-adenin-9-yl,1-deaza-guanin-9-yl, 1-deaza-inosin-9-yl, 1-deaza-2-amino-purin-9-yl,1-deaza-2-amino-6-chloro-purin-9-yl, 1-deaza-2-6-diamino-purin-9-yl,3-deaza-adenin-9-yl, 3-deaza-guanin-9-yl, 3-deaza-inosin-9-yl,3-deaza-2-amino-purin-9-yl, 3-deaza-2-amino-6-chloro-purin-9-yl3-deaza-2-6-diamino-purin-9-yl, 7-deaza-adenin-9-yl,7-deaza-guanin-9-yl, 7-deaza-inosin-9-yl, 7-deaza-2-amino-purin-9-yl,7-deaza-2-amino-6-chloro-purin-9-yl, 7-deaza-2-6-diamino-purin-9-yl,7-deaza-8-aza-adenin-9-yl, 7-deaza-8-aza-guanin-9-yl,7-deaza-8-aza-inosin-9-yl, 7-deaza-8-aza-2-amino-purin-9-yl,7-deaza-8-aza-2-amino-6-chloro-purin-9-yl,7-deaza-8-aza-2-6-diamino-purin-9-yl, 8-aza-adenin-9-yl,8-aza-guanin-9-yl, 8-aza-inosin-9-yl, 8-aza-2-amino-purin-9-yl,8-aza-2-amino-6-chloro-purin-9-yl, 8-aza-2-6-diamino-purin-9-yl,2-aza-adenin-9-yl, 2-aza-guanin-9-yl, 2-aza-inosin-9-yl,2-aza-2-amino-purin-9-yl, 2-aza-2-amino-6-chloro-purin-9-yl,2-aza-2-6-diamino-purin-9-yl, 3-deaza-thymin-1-yl, 3-deaza-cytosin-1-yl,3-deaza-uracil-1-yl, 5-aza-thymin-1-yl, 5-aza-cytqosin-1-yl,5-aza-uracil-1-yl, 6-aza-thymin-1-yl, 6-aza-cytosin-1-yl,6-aza-uracil-1-yl each of which is unsubstituted or substituted by atleast one of NHR₃, C₁₋₆alkyl, —OC₁₋₆alkyl, Br, Cl, F, I or OH, whereinR₃ is H, C₁₋₆alkyl or C₁₋₆acyl.

[0034] In one embodiment, B is chosen from adenin-9-yl, guanin-9-yl,inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl,2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl, uracil-1-yl,3-carboxamido-1,2,4-triazol-1-yl, 3-deaza-adenin-9-yl,3-deaza-guanin-9-yl, 3-deaza-inosin-9-yl, 3-deaza-2-amino-purin-9-yl,3-deaza-2-amino-6-chloro-purin-9-yl 3-deaza-2-6-diamino-purin-9-yl,7-deaza-adenin-9-yl, 7-deaza-guanin-9-yl, 7-deaza-inosin-9-yl,7-deaza-2-amino-purin-9-yl, 7-deaza-2-amino-6-chloro-purin-9-yl,7-deaza-2-6-diamino-purin-9-yl, 7-deaza-8-aza-adenin-9-yl,7-deaza-8-aza-guanin-9-yl, 7-deaza-8-aza-inosin-9-yl,7-deaza-8-aza-2-amino-purin-9-yl,7-deaza-8-aza-2-amino-6-chloro-purin-9-yl,7-deaza-8-aza-2-6-diamino-purin-9-yl, 8-aza-adenin-9-yl,8-aza-guanin-9-yl, 8-aza-inosin-9-yl, 8-aza-2-amino-purin-9-yl,8-aza-2-amino-6-chloro-purin-9-yl, 8-aza-2-6-diamino-purin-9-yl,2-aza-adenin-9-yl, 2-aza-guanin-9-yl, 2-aza-inosin-9-yl,2-aza-2-amino-purin-9-yl, 2-aza-2-amino-6-chloro-purin-9-yl,2-aza-2-6-diamino-purin-9-yl, 3-deaza-thymin-1-yl, 3-deaza-cytosin-1-yl,3-deaza-uracil-1-yl, 5-aza-thymin-1-yl, 5-aza-cytosin-1-yl,5-aza-uracil-1-yl, 6-aza-thymin-1-yl, 6-aza-cytosin-1-yl,6-aza-uracil-1-yl each of which is unsubstituted or substituted by atleast one of NHR₃, C₁₋₆alkyl, —OC₁₋₆alkyl, Br, Cl, F, I or OH, whereinR₃ is H, C₁₋₆alkyl or C₁₋₆acyl.

[0035] In one embodiment, B is chosen from adenin-9-yl, guanin-9-yl,inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl,2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl, uracil-1-yl,3-carboxamido-1,2,4-triazol-1-yl, 3-deaza-adenin-9-yl,3-deaza-guanin-9-yl, 3-deaza-inosin-9-yl, 3-deaza-2-amino-purin-9-yl,3-deaza-2-amino-6-chloro-purin-9-yl 3-deaza-2-6-diamino-purin-9-yl,7-deaza-adenin-9-yl, 7-deaza-guanin-9-yl, 7-deaza-inosin-9-yl,7-deaza-2-amino-purin-9-yl, 7-deaza-2-amino-6-chloro-purin-9-yl,7-deaza-2-6-diamino-purin-9-yl, 7-deaza-8-aza-adenin-9-yl,7-deaza-8-aza-guanin-9-yl, 7-deaza-8-aza-inosin-9-yl,7-deaza-8-aza-2-amino-purin-9-yl,7-deaza-8-aza-2-amino-6-chloro-purin-9-yl,7-deaza-8-aza-2-6-diamino-purin-9-yl, 8-aza-adenin-9-yl,8-aza-guanin-9-yl, 8-aza-inosin-9-yl, 8-aza-2-amino-purin-9-yl,8-aza-2-amino-6-chloro-purin-9-yl, 8-aza-2-6-diamino-purin-9-yl,5-aza-thymin-1-yl, 5-aza-cytosin-1-yl, 5-aza-uracil-1-yl,6-aza-thymin-1-yl, 6-aza-cytosin-1-yl, 6-aza-uracil-1-yl

[0036] each of which is unsubstituted or substituted by at least one ofNHR₃, C₁₋₆alkyl, —OC₁₋₆alkyl, Br, Cl, F, I or OH, wherein —R₃ is H,C₁₋₆alkyl or C₁₋₆acyl.

[0037] In one embodiment, B is chosen from adenin-9-yl, guanin-9-yl,inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl,0.2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl, uracil-1-yl,3-carboxamido-1,2,4-triazol-1-yl each of which is unsubstituted orsubstituted by at least one of NHR₃, C₁₋₆alkyl, —OC₁₋₆alkyl, Br, Cl, F,I or OH, wherein R₃ is H, C₁₋₆alkyl or C₁₋₆acyl.

[0038] In a further embodiment, B is chosen from adenin-9-yl,guanin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl,2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl, uracil-1-yl, each ofwhich is unsubstituted or substituted by at least one of NHR₃,C₁₋₆alkyl, —OC₁₋₆alkyl, Br, Cl, F, I or OH, wherein R₃ is H, C₁₋₆alkylor C₁₋₆acyl.

[0039] In a further embodiment, B is chosen from guanin-9-yl,cytosin-1-yl, uracil-1-yl, each of which is unsubstituted or substitutedby at least one of NHR₃, —C₁₋₆alkyl, —OC₁₋₆alkyl, Br, Cl, F, I or OH,wherein R₃ is H, C₁₋₆alkyl or C₁₋₆acyl.

[0040] In a further embodiment, B is cytosin-1-yl, which isunsubstituted or substituted by at least one of NHR₃, C₁₋₆alkyl, Br, Cl,F, I or OH, wherein R₃ is H, C₁₋₆alkyl or C₁₋₆acyl.

[0041] In a further embodiment, B is guanin-9-yl, which is unsubstitutedor substituted by at least one of NHR₃, C₁₋₆alkyl, Br, Cl, F, I or OH,wherein R₃ is H, C₁₋₆alkyl or C₁₋₆acyl.

[0042] In a further embodiment, B is uracil-1-yl, which is unsubstitutedor substituted by at least one of NHR₃, C₁₋₆alkyl, Br, Cl, F, I or OH,wherein R₃ is H, C₁₋₆alkyl or C₁₋₆acyl.

[0043] In one embodiment, B is chosen from adenin-9-yl, guanin-9-yl,inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl,2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl,5-fluoro-cytosin-1-yl, uracil-1-yl, 5-fluorouracil or1,2,4-triazole-3-carboxamide base (ribarivin base).

[0044] In one embodiment, B is chosen from adenin-9-yl, guanin-9-yl,inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl,2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl,5-fluoro-cytosin-1-yl, uracil-1-yl, or 1,2,4-triazole-3-carboxamide base(ribarivin base).

[0045] In one embodiment, B is chosen from guanin-9-yl, cytosin-1-yl,5′-fluoro-cytosin-1-yl, 5′-fluorouracil-1-yl or uracil-1-yl.

[0046] In one embodiment, B is chosen from guanin-9-yl, cytosin-1-yl,5′-fluoro-cytosin-1-yl, 5′-fluorouracil-1-yl or uracil-1-yl.

[0047] In one embodiment, B is cytosin-1-yl.

[0048] In one embodiment, B is 5-fluoro-cytosin-1-yl.

[0049] In one embodiment, B is 5-fluorouracil.

[0050] In one embodiment, B is guanin-9-yl.

[0051] In oneembodiment, B is uracil-1-yl.

[0052] In a further embodiment, B is

[0053] Wherein;

[0054] X is H, halogen or NHR₁₀, wherein R₁₀ is H, C₁₋₆acyl, C₁₋₆ alkyl,C₂₋₆ alkenyl, or C₂₋₆ alkynyl;

[0055] Y is H, halogen or NHR₁₁, wherein R₁₁ is H, C₁₋₆acyl, C₁₋₆ alkyl,C₂₋₆ alkenyl, or C₂₋₆ alkynyl;

[0056] Y₂ is H, halogen or NHR₁₂, wherein R₁₂ is H, C₁₋₆acyl, C₁₋₆alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;

[0057] R₉ is H, hydroxy protecting group, C₁₋₆acyl, C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl;

[0058] Y₃ is H, halogen or NHR₁₃, wherein R₁₃ is H, C₁₋₆acyl, C₁₋₆alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;

[0059] R₇ is H, halogen, C₁₋₆acyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl;

[0060] R₈ is H, halogen, C₁₋₆acyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl.

[0061] In one embodiment,

[0062] X is H, halogen or NHR₁₀, wherein R₁₀ is H.

[0063] Y is H, halogen or NHR₁₁, wherein R₁, is H.

[0064] Y₂ is H, halogen or NHR₁₂, wherein R₁₂ is H.

[0065] R₉ is H, hydroxy protecting group, C₁₋₆ alkyl.

[0066] Y₃ is H, halogen or NHR₁₃, wherein R₁₃ is H.

[0067] R₇ is H, halogen, or C₁₋₆ alkyl.

[0068] Re is H, halogen or C₁₋₆ alkyl.

[0069] In a further embodiment,

[0070] X is H, F, or NHR₁₀ wherein R₁₀ is H.

[0071] Y is H, F, or NHR₁₁, wherein R₁₁ is H.

[0072] Y₂ is H, F, or NHR₁₂, wherein R₁₂ is H.

[0073] R₉ is H.

[0074] Y₃ is H, F, or NHR₁., wherein R₁₃ is H.

[0075] R₇ is H, F, or C₁₋₆ alkyl.

[0076] R₈ is H, F, or C₁₋₆ alkyl.

[0077] In one embodiment of the invention, Ra is chosen from H,monophosphate, diphosphate, and triphosphate.

[0078] In another embodiment of the invention, Ra is H.

[0079] In one embodiment, Z is F or ORb, wherein Rb is chosen from of H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ acyl, or an hydroxyprotecting group.

[0080] In one embodiment, Z is F.

[0081] In one embodiment, Z is ORb, wherein Rb is chosen from of H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ acyl, or an hydroxy protectinggroup.

[0082] In one embodiment, Z is ORb, wherein Rb is chosen from of H, C₁₋₆alkyl, or an hydroxy protecting group.

[0083] In one embodiment, Z is ORb, wherein Rb ischosen from of H, ormethyl.

[0084] In one embodiment, Z is ORb, wherein Rb is H.

[0085] D₁ and D₂ are independently selected from N₃, F, or H, D and D₂can also be joined to be chosen from cyclopropyl,difluorocyclopropyl-═CH₂, or -═CF₂.

[0086] D₁ and D₂ are independently selected from F, or H, D₁ and D₂ canalso be joined to be chosen from cyclopropyl, difluorocyclopropyl-═CH₂,or -═CF₂.

[0087] D₁ and D₂ are joined and are cyclopropyl.

[0088] D₁ and D₂ are joined and are difluorocyclopropyl.

[0089] D₁ and D₂ are joined and are -═CH₂.

[0090] D₁ and D₂ are joined and are -═CF₂.

[0091] In one embodiment, D₁ is H or F.

[0092] In one embodiment, D₂ is H or F.

[0093] In one embodiment, D₁ is H.

[0094] In one embodiment, D₂ is H.

[0095] In one embodiment, D₁ is F.

[0096] In one embodiment, D₂ is F.

[0097] In one embodiment, D₁ is N₃ and D₂ is H.

[0098] In one embodiment, D₁ is H and D₂ is N₃.

[0099] In one embodiment, D₁ is N₃ and D₂ is F.

[0100] In one embodiment, D₁ is F and D₂ is N₃.

[0101] In one embodiment, D₁ is H and D₂ is F.

[0102] In one embodiment, D₁ is F and D₂ is H.

[0103] In one embodiment, D₁ and D₂ are H.

[0104] In one embodiment, D₁ and D₂ are F.

[0105] In a further embodiment, the present invention relates to amethod for the treatment or prevention of Flavivirus infections usingnucleoside analogues in a host comprising administering atherapeutically effective amount of a compound having the formula Ib ora pharmaceutically acceptable salt thereof:

[0106] wherein Ra, B, D₁, D₂ and Z are as defined above.

[0107] In a further embodiment, the present invention relates toa methodfor the treatment or prevention of Flavivirus infections usingnucleoside analogues in a host comprising administering atherapeutically effective amount of a compound having the formula Ic ora pharmaceutically acceptable salt thereof:

[0108] wherein Ra, B, D₁, D₂ and Z are as defined above.

[0109] In a further embodiment, the present invention relates to amethod for the treatment or prevention of Flavivirus infections usingnucleoside analogues in a host comprising administering atherapeutically effective amount of a compound having the formula Id ora pharmaceutically acceptable salt thereof:

[0110] wherein Ra, B, D₁, D₂ and Z are as defined above.

[0111] In a further embodiment, the present invention relates to amethod for the treatment- or prevention of Flavivirus infections usingnucleoside analogues in a host comprising administering atherapeutically effective amount of a compound having the formula Ie ora pharmaceutically acceptable salt thereof:

[0112] wherein Ra, B, D₁, D₂ and Z are as defined above.

[0113] In a further embodiment, the present invention relates to amethod for the treatment or prevention of Flavivirus infections usingnucleoside analogues in a host comprising administering atherapeutically effective amount of a compound having the formula If ora pharmaceutically acceptable salt thereof:

[0114] wherein Ra, B, and Z are as defined above.

[0115] In a further embodiment, the present invention relates to amethod for the treatment or prevention of Flavivirus infections usingnucleoside analogues in a host comprising administering atherapeutically effective amount of a compound having the formula Ig ora pharmaceutically acceptable salt thereof:

[0116] wherein Ra, B, and Z are as defined above.

[0117] In a further embodiment, the present invention relates to amethod for the treatment or prevention of Flavivirus infections usingnucleoside analogues in a host comprising administering atherapeutically effective amount of a compound having the formula Ih ora pharmaceutically acceptable salt thereof:

[0118] wherein Ra, B, and Z are as defined above.

[0119] In a further embodiment, the present invention relates to amethod for the treatment or prevention of Flavivirus infections usingnucleoside analogues in a host comprising administering atherapeutically effective amount of a compound having the formula Ii ora pharmaceutically acceptable salt thereof:

[0120] wherein Ra, B, and Z are as defined above.

[0121] In one embodiment, a compound of formula (I) is chosen from:3′-deoxycytidine Z = H, Compound #1, 3′-deoxycytidine- 5′triphosphate Z= triphosphate, Compound #2

5-Fluoro- 3′-deoxycytidine Z = H, Compound #3 5-Fluoro-3′-deoxycytidine- 5′triphosphate Z = triphosphate, Compound #4

3′-deoxyuridine Z = H, Compound #5 3′-deoxyuridine- 5′triphosphate Z =triphosphate, Compound #6

5-Fluoro- 3′-deoxyuridine Z = H, Compound #7 5-Fluoro- 3′-deoxyuridine-5′triphosphate Z = triphosphate, Compound #8

3′-deoxythymidine Z = H, Compound #9 3′-deoxythymidine- 5′triphosphate Z= triphosphate, Compound #10

3′-deoxyguanosine Z = H, Compound #11 3′-deoxyguanosine- 5′triphosphateZ = triphosphate, Compound #12

2-N-acetyl- 3′-deoxyguanosine Z = H, Compound #13 2-N-acetyl-3′-deoxyguanosine- 5′triphosphate Z = triphosphate, Compound #14

5-Methyl- 3′-deoxycytidine Z = H, Compound #15, 5-Methyl-3′-deoxycytidine- 5′triphosphate Z = triphosphate, Compound #16

5-Iodo- 3′-deoxycytidine Z = H, Compound #17, 5-Iodo- 3′-deoxycytidine-5′triphosphate Z = triphosphate, Compound #18

5-Chloro- 3′-deoxycytidine Z = H, Compound #19, 5- = Chloro-3′-deoxycytidine- 5′triphosphate Z = triphosphate, Compound #20

3′-fluoro- 3′-deoxyguanosine Z = H, Compound #21 3′-fluoro-3′-deoxyguanosine- 5′triphosphate Z = triphosphate, Compound #22

3′-fluoro- 3′-deoxycytidine Z = H, Compound #23, 3′-fluoro-3′-deoxycytidine- 5′triphosphate Z = triphosphate, Compound #24

5-Iodo- 3′-deoxycytidine Z = H, Compound #25, 5- = Iodp-3′-deoxycytidine- 5′triphosphate Z = triphosphate, Compound #26

5-Chloro- 3′-deoxyuridine Z = H, Compound #27 5-Chloro- 3′-deoxyuridine-5′triphosphate Z = triphosphate, Compound #28

5-Bromo- 3′-deoxyuridine Z = H, Compound #29 5-Bromo- 3′-deoxyuridine-5′triphosphate Z = triphosphate, Compound #30

6-Chloro- 3′-deoxyguanosine Z = H, Compound #31 6-Chloro-3′-deoxyguanosine- 5′triphosphate Z = triphosphate, Compound #32

3′-spirocyclopropyl- 3′-deoxyguanosine Z = H, Compound #333′-spirocyclopropyl- 3′-deoxyguanosine 5′triphosphate Z = triphosphate,Compound #34

3′-difluoro- spirocyclopropyl- 3′-deoxyguanosine Z = H, Compound #353′difluoro- spirocyclopropyl- 3′-deoxyguanosine 5′triphosphate Z =triphosphate, Compound #36

3′-methylene- 3′-deoxyguanosine Z = H, Compound #37 3′-methylene-3′-deoxyguanosine 5′triphosphate Z = triphosphate, Compound #38

3′-difluromethylene 3′-deoxyguanosine Z = H, Compound #393′-difluromethylene 3′-deoxyguanosine 5′triphosphate Z = triphosphate,Compound #40

3′-spiro- cyclopropyl- 3′-deoxycy- tidine Z = H, Compound #41 3′-spiro-cyclopropyl- 3′-deoxycy- tidine-5′triphosphate Z = triphosphate Compound#42

3′-difluoro- spirocyclopropyl- 3′- deoxycytidine Z = H, Compound #433′-difluoro- spirocyclopropyl- 3′-deoxycytidine- 5′triphosphate Z =triphosphate, Compound #44

3′-methylene- 3′-deoxycytidine Z = H, Compound #45 3′-methylene-3′-deoxycytidine- 5′triphosphate Z = triphosphate, Compound #46

3′-difluromethylene 3′-deoxycytidine Z = H, Compound #473′-difluromethylene 3′-deoxycytidine- 5′triphosphate Z = triphosphate,Compound #48

9-β-D-xylofuranosyl- guanosine Z = H, Compound #49 9-β-D-xylofuranosyl-guanosine- 5′triphosphate Z = triphosphate, Compound #50

9-β-D-xylofuranosyl- cytidine Z = H, Compound #51 9-β-D-xylofuranosyl-cytidine- 5′triphosphate Z = triphosphate, Compound #52

3′-azido- 3′-deoxycytidine Z = H, Compound #53 3′-azido-3′-deoxycytidine 5′triphosphate Z = triphosphate, Compound #54

[0122] It will be appreciated by those skilled in the art that thecompounds of formula (I) contain at least three chiral centres and whichare marked by 1, 2 and 3. When D₁ and D₂ are different, the compounds offormula (I) contain at least four chiral centres which are marked by 1,2, 3 and 4. The compounds of formula (I) thus exist in the form ofdifferent optical isomers (e.g β-L and β-D) and geometric isomers transor α and cis or β. All such enantiomers, geometric isomers and mixturesthereof including racemic mixtures are included within the scope of theinvention. The single optical isomer or enantiomer can be obtained bymethod well known in the art, such as chiral HPLC, enzymatic resolutionand the use of chiral auxiliary.

[0123] According to one embodiment, the atoms marked by 1 and 2 are inthe cis or β configuration.

[0124] According to one embodiment, the atoms marked by 1 and 2 are inthe cis or β configuration while the atom marked by 3 is in a trans or αconfiguration with respect to the atom 1 and 2.

[0125] According to one embodiment, compounds of formula I of thepresent invention are provided substantially in the form of the β-Dconfiguration.

[0126] According to one embodiment, compounds of formula I of thepresent invention are provided substantially in the form of the β-Lconfiguration.

[0127] By “substantially” is meant that there is more one enantiomerthen of the other enantiomer.

[0128] In another embodiment, the compounds of formula I of the presentinvention are at least 95% free of the corresponding β-D enantiomer.

[0129] In another embodiment, the compounds of formula I of the presentinvention are at least 97% free of the corresponding β-D enantiomer.

[0130] Still in another embodiment, the compounds of formula I of thepresent invention are at least-99% free of the corresponding β-Denantiomer.

[0131] In another embodiment, the compounds of formula I of the presentinvention are at least 95% free of—the corresponding β-L enantiomer.

[0132] In another embodiment, the compounds of formula I of the presentinvention are at least 97% free of the corresponding β-L enantiomer.

[0133] Still in another embodiment, the compounds of formula I of thepresent invention are at least 99% free of the corresponding β-Lenantiomer.

[0134] There is also provided pharmaceutically acceptable salts of thecompounds of formula I of the present invention. By the termpharmaceutically acceptable salts of the compounds of formula (I) aremeant those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric,maleic, phosphoric, glycollic, lactic, salicylic, succinic,toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic,benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.

[0135] Salts derived from appropriate bases include alkali metal (e.g.sodium), alkaline earth metal (e.g. magnesium), ammonium and NR₄+ (whereR is C₁₋₄ alkyl) salts.

[0136] Unless otherwise defined, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. All publications,patent applications, patents, and other references mentioned herein areincorporated by reference in their entirety. In case of conflict, thepresent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and notintended to be limiting.

[0137] As used in the present application, “compound(s) of formula (I)”refers to all compounds identified by formula (I) and formulae (Ia) to(Ii).

[0138] As used in this application, the term “purine or pyrimidine or ananalogue thereof” is meant a purine or pyrimidine base found innucleotide or an analogue thereof which mimics such bases in that theirstructures (the kinds of atoms and their arrangement) are similar to thenormal bases but may possess additional or lack certain of thefunctional properties of the normal bases. Such analogues include thosederived by replacement of a CH moiety by a nitrogen atom (for example,5-azapyrimidines such as 5-azacytosine) or vice versa (for example7-deazapurines, such as 7-deazadenosine or 7-deazaguanosine) or both(e.g. 7-deaza, 8-azapurines). Analogues of such bases also include thosecompounds wherein ring substituents are either incorporated, removed ormodified by conventional substituents known in the art e.g. halogen,hydroxyl, amino, C1-6 alkyl. Such purine or pyrimidine base, analoguesand derivatives will be well known to those skilled in the art.

[0139] As used in this application, the term “alkyl” represents anunsubstituted or substituted (by a halogen, nitro, CONH₂, COOH, O—C₁₋₆alkyl, O—C₂₋₆ alkenyl, O—C₂₋₆ alkynyl, hydroxyl, amino, or COOQ, whereinQ is C₁₋₆ alkyl; C₂₋₆ alkenyl; C₂₋₆ alkynyl) straight chain, branchedchain or cyclic hydrocarbon moiety (e.g. isopropyl, ethyl, fluorohexylor cyclopropyl). The term alkyl is also meant to include alkyls in whichone or more hydrogen atoms is replaced by an halogen, more preferably,the halogen is fluoro (e.g. CF₃— or CF₃CH₂—)

[0140] As used in this application, the term “cycloalkyl” represents an“alkyl” as defined above which forms a ring.

[0141] The terms “alkenyl” and “alkynyl” represent an alkyl containingat least one unsaturated group (e.g. allyl).

[0142] The term “hydroxy protecting group” is well known in the field oforganic chemistry. Such protecting groups may be found in T. Greene,Protective Groups In Organic Synthesis, (John Wiley & Sons, 1981).Example of hydroxy protecting groups include but are not limited toacetyl-2-thioethyl ester, pivaloyloxymethyl ester andisopropyloxycarbonyloxymethyl ester.

[0143] The term “aryl” represents an unsaturated carbocyclic moiety,optionally mono- or di-substituted with OH, SH, amino, halogen or C₁₋₆alkyl.

[0144] The term “heteroaryl” represents an aryl wherein at least onecarbon ring atom is substituted by an heteroatom (e.g. N, O, or S).

[0145] The term “aminoalkyl” represents an alkyl which is covalentlybonded to the adjacent atom through a nitrogen atom.

[0146] The term “thioalkyl” represents an alkyl which is covalentlybonded to the adjacent atom through a sulfur atom.

[0147] The term “alkoxy” represents an alkyl which is covalently bondedto the adjacent atom through an oxygen atom.

[0148] Halogen are chosen from F, Cl, I, and Br.

[0149] The term “host” represents any mammals including humans.

[0150] In one embodiment, the host is human.

[0151] The compounds of the present invention are can be prepared bymethods well known in the art. For example, such methods are describedin the following references J.Med.Chem. 1991, 34, 693-701; Chem. Pharm.Bull. 1995, 43(11) 2005-2009; J.Org.Chem. 1989, 54, 631-635; Can.J.Chem.1975, 53(19), 2975-2977; Nucleosides Nucleotides, 1990, 9(8), 1045-60and Chemistry of Nucleosides and Nucleotides edited by Leroy B. Towsend,1988 Plenum Press Volumes 1 and 2; Synthesis of 2′-β-fluoro- and3′-β-fluoro-substituted guanine nucleosides. Effect of sugarconformational shifts on nucleophilic displacement of the 2′-hydroxy and3′-hydroxy group with DAST. J. Org. Chem., 57(26), (1992) 7315-21.Synthesis and antiviral and cytostatic properties of 3′-deoxy-3′-fluoro-and 2′-azido-3′-fluoro-2′,3′-dideoxy-D-ribofuranosides of naturalheterocyclic bases. J. Med. Chem. 34(7), (1991) 2195-202. Synthesis of9-(3-deoxy-3-fluoro-β-D-ribofuranosyl)guanine, a new potent antiviralagent. J. Chem. Soc., Chem. Commun. (1989) (1989), (14), 955-7.Synthesis and antiviral activity evaluation of3′-fluoro-3′-deoxyribonucleosides: broad-spectrum antiviral activity of3′-fluoro-3′-deoxyadenosine. Antiviral Res. (1989), 12(3), 133-50.3′-Fluoro-3′-deoxyribonucleoside 5′-triphosphates: synthesis and use asterminators of RNA biosynthesis. FEBS Lett. (1989), 0.250(2), 139-41.Reaction of 1-(2′,3′-epoxy-β-D-lyxofuranosyl)uracil with hydrogenfluoride. The unexpected formation of1-(3′-fluoro-3′-deoxy-β-D-ribofuranosyl)uracil. J. Heterocycl. Chem.(1989), 21(3), 773-5. Synthesis of 3′-deoxy-3′-fluorouridine. J.Carbohydr., Nucleosides, Nucleotides (1989), 2(3), 191-5. Synthesis ofthe 2′-deoxy-21-fluoro and 3′-deoxy-3′-fluoro analogs of8-bromoadenosine. Nucleic Acids Symp. Ser. (1989), 37(Symposium onNucleic Acids Chemistry, 1997), 17-18. Synthesis of 8-substitutedanalogs of 3′-deoxy-31-fluoroadenosine. Nucleosides Nucleotides (1989),0.17(1-3), 115-122. A new synthesis of 3′-fluoro-3′-deoxyadenosine.Nucleosides Nucleotides (1989), 10(1-3), 719-21. Synthesis of3′-fluoro-3′-deoxyadenosine starting from adenosine. Synthesis (1989),(10), 900-5. Synthesis of 3′-deoxy-3′-fluoroadenosine by chemicaltransglycosidation. Z. Chem. (1989), 29(6); 209-10. Stereoselectivesynthesis of 3′-deoxy-3′-fluoroadenosine. Bull. Chem. Soc. Jpn. (1989),62(6), 2119-20. Synthesis of nucleosides fluorinated in the sugarmoiety. The application of diethylaminosulfur trifluoride to thesynthesis of fluorinated nucleosides. Nucleosides Nucleotides (1989),8(1), 65-96. Preparation of difluorouridines as antitumor agents.Efficient removal of sugar O-tosyl groups and heterocycle halogens frompurine nucleosides with sodium naphthalenide. Tetrahedron (1989),53(18), 6295-6302. Synthesis of fluoro and azido derivatives of purinenucleosides from nucleoside 2′,3′-cyclic sulfates. Bioorg. Khim. (1989),20(11), 1226-30. Synthesis of modified oligomeric 2′-5′ A analogs:potential antiviral agents. Helv. Chim. Acta (1989), 74(1), 7-23.Diethylaminosulfur trifluoride (DAST) as a fluorinating agent ofpyrimidine nucleosides having a 2′,3′-vicinal diol system. Chem. Pharm.Bull. (1989), 38(5), 1136-9. Synthesis of 9-(3-deoxy- and2,3-dideoxy-3-fluoro-β-D-xylofuranosyl)guanines as potential antiviralagents. Tetrahedron Lett. (1989), 30(24), 3171-4. Synthesis and anti-HIVactivity of various 2′- and 3′-substituted 2′,3′-dideoxyadenosines: astructure-activity analysis. J. Med. Chem. (1989)., 30(11), 2131-7.Adenosine 2′,3′-ribo-epoxide. Synthesis, intramolecular degradation, andtransformation into 3′-substituted xylofuranosyl nucleosides and thelyxo-epoxide. J. Org. Chem. (1989), 39(11), 1564-70. Fluoro sugaranalogs of arabinosyl- and xylosylcytosines. J. Med. Chem. (1989),13(2), 269-72. 9-(3-Deoxy-3-fluoro-β-D-xylofuranosyl)adenine and9-(3-deoxy-3-fluoro-β-D-arabinofuranosyl)adenine. Carbohyd. Res. (1989),6(3), 347-54. 3′,3′-Difluoro-3¹-deoxythymidine: comparison of anti-HIVactivity to 3′-fluoro-3′-deoxythymidine. J. Med. Chem. (1989), 35(18),3369-72. Nucleic acid related compounds. 83. Synthesis of3′deoxyadenosine-3′-spirocyclopropane,31-deoxyuridine-3′-spirocyclopropane, and5′-deoxy-4′,51-methanoadenosine. Tetrahedron Lett. (1989), 35(21),3445-8. Synthesis of 2′,3′-didehydro-21,31-dideoxy-3′-C-methylsubstituted nucleosides. Nucleosides Nucleotides (1989), 12(8), 865-77.2′,3′-Didehydro-2′,3′-dideoxy-2′(and3′)-methylnucleosides via[3,3]-sigmatropic rearrangements of 2′(and 3′)-methylene-3¹′(and2′)—O-thiocarbonyl derivatives and radical reduction of a2′-chloro-3¹-methylene analog. Can. J. Chem. (1989), 71(2), 186-91.Synthesis and biological activity of 2′ (and 3′)-deoxy-2¹ (and3′)-methylenenucleoside analogs that function as mechanism-basedinhibitors of S-adenosyl-L-homocysteine hydrolase and/or ribonucleotidereductase. J. Med. Chem. (1989), 35(12), 2283-93. Synthesis andanticancer and antiviral activities of various 2′- and3′-methylidene-substituted nucleoside analogs and crystal structure of2′-deoxy-2′-methylidenecytidine hydrochloride. J. Med. Chem. (1989),34(8), 2607-15. Stereoselective addition of a Wittig reagent to give asingle nucleoside oxaphospetane diastereoisomer. Synthesis of 2′ (and3′)-deoxy-2′ (and 3′)-methyleneuridine (and cytidine) derivatives fromuridine ketonucleosidesSynthesis (1989), (4), 282-8. A novel example ofunsaturated branched chain sugar nucleoside:3′-deoxy-3′-methylideneadenosine. Helv. Chim. Acta (1989), 64(2), 425-9.Synthesis of 2′ (and 3′)-deoxy-2′ (and 3′)-methyleneadenosines andbis(methylene)furan 4′,5′-didehydro-5′-deoxy-2′(and3¹)-methyleneadenosines. Inhibitors of S-adenosyl-L-homocysteinehydrolase and ribonucleotide reductase. J. Org. Chem. (1989), 56(25),7108-13. Radical and palladium-catalyzed deoxygenation of the allylicalcohol systems in the sugar moiety of pyrimidine nucleosides.Nucleosides Nucleotides (1989), 11(2-4), 197-226. Synthesis and NMRspectra of some new carbohydrate modified uridine phosphoramidites.Nucleosides Nucleotides (1989), 16(7-9), 1529-1532. New method for thepreparation of 3′- and 2′-phosphoramidites of 2′- and3′-difluoromethyleneuridine. Tetrahedron (1989), 52(23), 7929-7938.Nucleic acid related compounds. 83. Synthesis of3′deoxyadenosine-3′-spirocyclopropane,3′-deoxyuridine-3′-spirocyclopropane, and5′-deoxy-4′,5′-methanoadenosine. Tetrahedron Lett. (1989), 35(21),3445-8. Some compounds of the present invention are commerciallyavailable at Sigma or Aldrich.

[0152] According to one embodiment, it will be appreciated that theamount of a compound of formula I of the present invention required foruse in treatment will vary not only with the particular compoundselected but also with the route of administration, the nature of thecondition for which treatment is required and the age and condition ofthe patient and will be ultimately at the discretion of the attendantphysician or veterinarian. In general however a suitable dose will be inthe range of from about 0.01 to about 750 mg/kg of body weight per day,preferably in the range of 0.5 to 60 mg/kg/day, most preferably in therange of 1 to 20 mg/kg/day.

[0153] The desired dose according to one embodiment is convenientlypresented in a single dose or as divided dose administered atappropriate intervals, for example as two, three, four or more doses perday.

[0154] In another embodiment, the compound is conveniently administeredin unit dosage form; for example containing 10 to 1500 mg, conveniently20 to 1000 mg, most conveniently 50 to 700 mg of active ingredient perunit dosage form.

[0155] According to another embodiment of the present invention, theactive ingredient is administered to achieve peak plasma concentrationsof the active compound of from about 1 to about 75 μM, preferably about2 to 50 μM, most preferably about 3 to about 30 μM. This may beachieved, for example, by the intravenous injection of a 0.1 to 5%solution of the active ingredient, optionally in saline, or orallyadministered as a bolus containing about 1 to about 500 mg of the activeingredient. Desirable blood levels may be maintained by a continuousinfusion to provide about 0.01 to about 5.0 mg/kg/hour or byintermittent infusions containing about 0.4 to about 15 mg/kg of theactive ingredient.

[0156] While it is possible that, for use in therapy, a compound offormula I of the present invention may be administered as the rawchemical, it is preferable according to one embodiment of the invention,to present the active ingredient as a pharmaceutical formulation. Theembodiment of the invention thus further provides a pharmaceuticalformulation comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof together with one or more pharmaceuticallyacceptable carriers therefor and, optionally, other therapeutic and/orprophylactic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof. According to oneembodiment of the present invention, pharmaceutical formulations includebut are not limited to those suitable for oral, rectal, nasal, topical(including buccal and sub-lingual), transdermal, vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.The formulations may, where appropriate, be conveniently presented indiscrete dosage units and may be prepared by any of the methods wellknown in the art of pharmacy. All methods according to this embodimentinclude the step of bringing into association the active compound withliquid carriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation.

[0157] According to another embodiment, pharmaceutical formulationsuitable for oral administration are conveniently presented as discreteunits such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient; as a powder or granules.In another embodiment, the formulation is presented as a solution, asuspension or as an emulsion. Still in another embodiment, the activeingredient is presented as a bolus, electuary or paste.

[0158] Tablets and capsules for oral administration may containconventional excipients such as binding agents, fillers, lubricants,disintegrants, or wetting agents. The tablets may be coated according tomethods well known in the art. Oral liquid preparations may be in theform of, for example, aqueous or oily suspensions, solutions, emulsions,syrups or elixirs, or may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may contain conventional additives such as suspendingagents, emulsifying agents, non-aqueous vehicles (which may includeedible oils), or preservatives.

[0159] The compounds of formula I according to an embodiment of thepresent invention are formulated for parenteral administration (e.g. byinjection, for example bolus injection or continuous infusion) and maybe presented in unit dose form in ampoules, pre-filled syringes, smallvolume infusion or in multi-dose containers with an added preservative.The compositions may take such forms as suspensions, solutions, oremulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilizing an/or dispersing agents.Alternatively, the active ingredient may be in powder form, obtained byaseptic isolation of sterile solid or by lyophilisation from solution,for constitution with a suitable vehicle, e.g. sterile, pyrogen-freewater, before use.

[0160] For topical administration to the epidermis, the compounds offormula I, according to one embodiment of the present invention, areformulated as ointments, creams or lotions, or as a transdermal patch.Such transdermal patches may contain penetration enhancers such aslinalool, carvacrol, thymol, citral, menthol and t-anethole. Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents. Lotionsmay be formulated with an aqueous or oily base and will in general alsocontain one or more emulsifying agents, stabilizing agents, dispersingagents, suspending agents, thickening agents, or colouring agents.

[0161] Formulations suitable for topical administration in the mouthinclude lozenges comprising active ingredient in a flavoured base,usually sucrose and acacia or tragacanth; pastilles comprising theactive ingredient in an inert base such as gelatin and glycerin orsucrose and acacia; and mouthwashes comprising the active ingredient ina suitable liquid carrier.

[0162] Pharmaceutical formulations suitable for rectal administrationwherein the carrier is a solid. In another embodiment, they arepresented as unit dose suppositories. Suitable carriers include cocoabutter and other materials commonly used in the art, and thesuppositories may be conveniently formed by admixture of the activecompound with the softened or melted carrier(s) followed by chilling andshaping in moulds.

[0163] According to one embodiment, the formulations suitable forvaginal administration are presented as pessaries, tampons, creams,gels, pastes, foams or sprays containing in addition to the activeingredient such carriers as are known in the art to be appropriate.

[0164] For intra-nasal administration the compounds, in one embodimentof the invention, are used as a liquid spray or dispersible powder or inthe form of drops. Drops may be formulated with an aqueous ornon-aqueous base also comprising one more dispersing agents,solubilising agents or suspending agents. Liquid sprays are convenientlydelivered from pressurized packs.

[0165] For administration by inhalation the compounds, according to oneembodiment of the invention are conveniently delivered from aninsufflator, nebulizer or a pressurized pack or other convenient meansof delivering an aerosol spray. In another embodiment, pressurized packscomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In another embodiment, the dosage unit in thepressurized aerosol is determined by providing a valve to deliver ametered amount.

[0166] Alternatively, in another embodiment, for administration byinhalation or insufflation, the compounds of formula I according to thepresent invention are in the form of a dry powder composition, forexample a powder mix of the compound and a suitable powder base such aslactose or starch. In another embodiment, the powder composition ispresented in unit dosage form in, for example, capsules or cartridges ore.g. gelatin or blister packs from which the powder may be administeredwith the aid of an inhalator or insufflator.

[0167] In one embodiment, the above described formulations are adaptedto give sustained release of the active ingredient.

[0168] The compounds of the invention may also be used in combinationwith other antiviral agents.

[0169] In one embodiment, the compounds of the invention may be employedtogether with at least one other antiviral agent chosen from proteaseinhibitors, polymerase inhibitors, and helicase inhibitors.

[0170] As used in this application, the term “interferon” include:interferon likes molecules such as interferon (IFN), interferon α-2a,interferon α-2b, consensus interferon (CIFN) and other types ofinterferons.

[0171] In one embodiment, the compounds of the invention may be employedtogether with at least one other antiviral agent chosen from interferon(IFN), interferon α-2a, interferon α-2b, consensus interferon (CIFN),ribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholicacid (UDCA), glycyrrhizin and silybum marianum.

[0172] In one embodiment, the compounds of the invention may be employedtogether with at least one other antiviral agent chosen fromInterferon-α, Ribavirin and Amantadine.

[0173] In one embodiment, the compounds of the invention may be employedtogether with at least one other antiviral agent chosen fromInterferon-α and Ribavirin (REBETRON).

[0174] In one embodiment, the compounds of the invention may be employedtogether Interferon-α.

[0175] In one embodiment, the compounds of the invention may be employedtogether with Ribavirin.

[0176] The combinations referred to above may conveniently be presentedfor use in the form of a pharmaceutical formulation and thuspharmaceutical formulations comprising a combination as defined abovetogether with a pharmaceutically acceptable carrier therefor comprise afurther aspect of the invention.

[0177] The individual components of such combinations may beadministered either sequentially or simultaneously in separate orcombined pharmaceutical formulations.

[0178] When the compound (I) or a pharmaceutically acceptable saltsthereof is used in combination with a second therapeutic agent activeagainst the same virus the dose of each compound may be either the sameas or differ from that when the compound is used alone.

[0179] Appropriate doses will be readily appreciated by those skilled inthe art.

[0180] The following examples are provided to illustrate variousembodiments of the present invention and shall not be considered aslimiting in scope.

EXAMPLE 1 Preparation of 3′-DEOXYCYTIDINE 5′-TRIPHOSPHATE TRIAMMONIUMSALT (Compound #2)

[0181]

[0182] Procedure: To a stirring suspension of3′-deoxy-2′-acetoxycytidine (15.0 mg, 0.056 mmol) in dry DMF (0.60 ml)was added dry pyridine (0.20 ml) followed by a freshly prepared solutionof 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one. 0. 5M in 1,4-dioxane(111 μl, 0.056 mmol). The mixture was stirred 30 minutes at roomtemperature, then tributylamine (36 μl, 0.152 mmol) and a solution oftributylammonium pyrophosphate 0.5 M in DMF (101 μl, 0.051 mmol) wereadded simultaneously. The mixture was stirred another 30 minutes. Asolution of I2 1% in pyridine/H₂O (98:2) (1.01 ml, 0.081 mmol of I) wasadded and the mixture was stirred 30 minutes. The excess of iodine wasdestroyed by adding 0.2 ml of aqueous sodium bisulfite 5%. The mixturewas stirred 15 minutes, then it was concentrated under reduced pressureto remove all solvents. The residue was dissolved in water, washed twotimes with methylene chloride and once with ethyl acetate. The aqueouslayer was concentrated and purified by charcoal column as follow: about400 mg of charcoal, placed over a thin layer of Celite in a funnel withfritted disk, was prewashed by passing methanol, then deionized water(by vaccuum). The crude residue was diluted in a minimum of water,acidified to pH 1-2 by adding few drops of HCl 1N, then placed on thetop of the charcoal column. The column was eluted with deionized water(35 ml) in order to remove inorganic salts, then 0.5 N ammonia (15 ml)to collect the desired triphosphate. The collected triphophatewasconcentrated and diluted in deionized water (1 ml) and concentratedNH4OH (2 ml). The mixture was stirred one hour at room temperature tocleave the acetyl group, then concentrated to dryness. The residue waspurified on a pad of C18 RP silica gel eluting with deionized water (thedesired triphosphate comes out fast). The fractions containing thedesired triphosphate were collected and lyophilized to give, the3′-deoxycytidine 5′-triphosphate triammonium salt as a yellowish solid(18 mg, 69% yield, purity>85% evaluated by 1H and 31P-NMR). ¹H NMR (400MHz, D₂O) δ: 7.90 (d, 1H, 7.5 Hz), 5.99 (d, 1H, 7.5 Hz), 5.73 (s, 1H),4.55 (s, 1H), 4.35 (d, 1H, 5.0 Hz), 4.26 (m, 1H), 4.04 (m, 1H), 2.05 (m,1H), 1.94 (m, 1H) ppm. ³¹P NMR (162 MHz, D₂O) δ: −5.9 (br.s), −10.4 (d,19 Hz), −21.5 (br.s) ppm. In a similar manner, the compounds of theinvention can be obtained.

EXAMPLE 2 Evaluation of Triphosphate Analogues

[0183] In The HCV RNA-Dependent RNA Polymerase AssayThe followingreferences which are referenced in the example are all incorporated byreference:

[0184] 1. Behrens, S., Tomei, L., De Francesco, R. (1989) EMBO 15, 12-22

[0185] 2. Harlow, E, and Lane, D. (1989) Antibodies: A LaboratoryManual. Cold Spring Harbord Laboratory. Cold Spring Harbord. NY.

[0186] 3. Lohmann, V., Korner, F., Herian, U., and Bartenschlager, R.(1989) J. Virol. 71, 8416-8428

[0187] Compounds were evaluated using an in vitro polymerase assaycontaining purified recombinant HCV RNA-dependent RNA polymerase (NS5Bprotein). HCV NS5B was expressed in insect cells using a recombinantbaculovirus as vector. The experimental procedures used for the cloning,expression and purification of the HCV NS5B protein are described below.Following are details of the RNA-dependent RNA polymerase assays used totest the compounds.

[0188] Expression of the HCV NS5B Protein in Insect Cells:

[0189] The cDNA encoding the entire NS5B protein of HCV-Bk strain,genotype 1b, was amplified by PCR using a plasmid containing a cDNAversion of the full-length HCV genome as template. The oligonucleotidesused to amplify this HCV region were designed to introduce a NheI sitefollowed by an ATG at the 5′ end of the NS5B coding region as well as aBamHI site at the 3′end immediately downstream of the translation stopcodon. The amplified sequence, of 1.8 kb, was digested with NheI andBamHI and ligated to a predigested pBlueBacII plasmid (Invitrogen). Theresulting recombinant plasmid was designated pBac/NS5B. Sf9 cells wereco-transfected with 3 μg of pBac/NS5B, together with 1 μg of linearizedbaculovirus DNA (Invitrogen), as described in the manufacturer'sprotocol. Following two rounds of plaque purification, anNS5B-recombinant baculovirus, BacNS5B, was isolated. The presence of therecombinant NS5B protein was determined by western blot analysis (Harlowand Lane, 1988) of BacNS5B-infected Sf9 cells, using a HCV NS5B specificrabbit polyclonal antiserum (anti-NS5B). Infections of Sf9 cells withthis plaque purified virus were performed in one-liter spinner flasks ata cell density of 1.2×10⁶ cells/ml and a multiplicity of infection of 5.

[0190] Preparation of a Soluble Recombinant NS5B Protein:

[0191] Sf9 cells were infected as described above. Sixty hourspost-infection, cells were harvested then washed twice with phosphatebuffer saline (PBS). Total proteins were solubilized as described inLohmann et al. (1989) with some modifications. In brief, proteins wereextracted in three steps, S1, S2, S3, using lysis buffers (LB) I, LB IIand LB III (Lohmann et al, 1997). The composition of LBII was modifiedto contain 0.1% triton X-100 and 150 mM NaCl to reduce the amount ofsolubilized NS5B protein at this step. In addition, sonication of cellextracts was avoided throughout the protocol to preserve the integrityof the protein structure.

[0192] Purification of Recombinant NS5B Using Fast Protein LiquidChromatography (FPLC):

[0193] Soluble NS5B protein in the S3 fraction was diluted to lower theNaCl concentration to 300 mM, then it incubated batchwise with DEAEsepharose beads (Amersham-Pharmacia) for 2 hrs at 0.4?C, as described byBehrens et al. (1989). Unbound material was cleared by centrifugationfor 15 min at 4° C., at 25 000 rpm using a SW41 rotor (Beckman). Thesupernatant was further diluted to lower the NaCl concentration to 200mM and subsequently loaded, with a flow rate of 1 ml/min, on a 5 mlHiTrap® heparin column (Amersham-Pharmacia) connected to an FPLC® system(Amersham-Pharmacia). Bound proteins were eluted in 1 ml fractions,using a continuous NaCl gradient of 0.2 to 1 M, over a 25 ml volume.NS5B-containing fractions were identified by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE), followed by westernblotting using the anti-NS5B antiserum at a dilution of 1:2000. Positivefractions were pooled and the elution buffer was exchanged against a 50mM NaPO₄ pH 7.0, 20% glycerol, 0.5% triton X-100 and 10 mM DTT, using aPD-10 column (Amersham-Pharmacia). The sample was then loaded onto a 1ml HiTrap® SP column (Amersham-Pharmacia), with a flow rate of 0.1ml/min. Bound proteins were eluted using a continuous 0 to 1 M NaClgradient over a 15 ml volume. Eluted fractions were analyzed by SDS-PAGEand western blotting. Alternatively, proteins were visualized, followingSDS-PAGE, by silver staining using the Silver Stain Plus kit (BiORad) asdescribed by the manufacturer. Positive fractions were tested for RdRpactivity (see below) and the most active ones were pooled, and stored asa 40% glycerol solution at −70° C.

[0194] In Vitro RNA-Dependent RNA Polymerase Assays Used to Evaluate theTriphosphate Form of Nucleoside Analogues:

[0195] RdRp assays were conducted using in vitro transcribedheteropolymeric RNA templates.

[0196] RdRp reactions were performed in a total volume of 50 μl of abuffer consisting of 20 mM Tris-HCl pH 7.5, 1 mM DTT, 50 mM NaCl, 0.5 mMMnCl₂ and 5 mM MgCl₂. Standard HCV RdRp reactions contained 200 ng ofpurified NS5B protein. The substrate mixture included in the, assaydepended on the base of the nucleoside triphosphate to be tested(adenine, guanine, cytosine or uracil analogue). The NTP substrate witha similar base to that of the inhibitor, was added at twice the measuredKm. This concentration included 5 uCi (3000 Ci/mmol) of a. [³²p] versionof this nucleotide. The remaining three substrates were used at 100 μM.The measured Kms for the four substrates were as follows: 18 μM for ATP,0.5 μM for CTP and GTP, and 1.2 μM for UTP. Following a two hourincubation at 22° C., reactions were stopped by the addition of 100 μgof sonicated salmon sperm DNA (Life Technologies) and 1 ml of 10%trichloroacetic acid (TCA)-0.5% tetrasodium pyrophosphate (PPi). Nucleicacids were precipitated at 4° C. for 30 min after which samples werefiltered on GF/C glass microfiber filters (Millipore). Membranes weresubsequently washed with 25 ml of a 1% TCA-0.1% PPi solution, then airdried. Incorporated radioactivity was quantified using a liquidscintillation counter (1450-Microbeta, Wallac).

[0197] Heteropolymeric RNA templates were generated by run-offtranscription. As template for these transcription reactions, arecombinant pcDNA3 plasmid (Invitrogen) containing a cDNA version of theHCV genome was used and referred to as pcDNA/HCVfl. In vitrotranscriptions were performed using the MEGAscript™ kit (Ambion), assuggested by the manufacturer. In brief, the plasmid pcDNA/HCVfl waslinearized with EcOR1 to generate a truncated HCV transcript of about6900 nucleotides. Linearized DNA was extracted with a one to one volumeof phenol/chloroform, precipitated with ethanol, then-1 μg of thislinearized DNA was used as template in T7 RNA polymerase-driven in vitrotranscription reactions. Transcripts were extracted using the TRIZOL®reagent (Life Technologies) and an aliquot (1 μg) was used as templatein RdRp assays. HCV polymerase Compound IC₅₀ COMPOUND#2 0.036 μMCOMPOUND#4 0.3 μM COMPOUND#6 0.26 μM COMPOUND#8 1.98 μM COMPOUND#10 6.4μM COMPOUND#12 0.048 μM COMPOUND#14 3.1 μM COMPOUND#16 0.36 μMCOMPOUND#18 6.88 μM COMPOUND#20 0.18 μM COMPOUND#22 0.12 μM COMPOUND#240.055 μM COMPQUND#26 0.91 μM COMPOUND#28 2.1 μM COMPOUND#30 2.9 μMCOMPOUND#32 6.8 μM COMPOUND#54 9.0 μM

1. A method for the treatment or prevention of an hepatitis C infectionin a host comprising administering to said host a therapeuticallyeffective amount of a compound having the formula Ib or apharmaceutically acceptable salt thereof:

wherein B is a nucleotide purine radical, a nucleotide pyrimidineradical or an analogue of a nucleotide purine radical or a nucleotidepyrimidine radical, wherein said analogue is derived by replacement of aCH moiety by a nitrogen atom in a nucleotide purine or pyrimidineradical, replacement of a nitrogen atom by a CH moiety in a nucleotidepurine or pyrimidine radical or both; or derived by removal of ringsubstituents of said nucleotide purine radical or pyrimidine radical; orcombinations thereof, and said analogue is optionally substituted byhalogen hydroxyl, amino or C₁₋₆ alkyl; Ra is H, monophosphate,diphosphate, triphosphate, carbonyl which is substituted by a straight,branched or cyclic alkyl having up to 6 C atoms wherein the alkyl isunsubstituted or substituted by halogen, nitro CONH, COOH O-CQ-6 alkylO—C₆ alkenyl O—C₆ alkynyl hydroxyl, amino or COOQ, C₂₋₆ alkenyl which isunsubstituted or substituted by halogen nitro, CONH₂, COOH, O—C_alkylO—C_alkenyl, O—C, alkynyl, hydroxyl, amino, or COOQ, C₂₋₆ alkynyl whichis unsubstituted or substituted by halogen, nitro, CONH, COOH. O—C₁₋₆alkyl O—C_alkenyl O—C₂₋₆ alkynyl, hydroxyl, amino, or COOQ, C₆₋₁₀ arylwhich is unsubstituted or mono- or di-substituted with OH SH, aminohalogen or C₁₋₆ alkyl, or an

Rc is in each case independently, H, straight chain, branched chain orcyclic C₁₋₆ alkyl which is unsubstituted or substituted by orsubstituted by halogen, nitro, CONH. COOH, O—C₁₋₆ alkyl O—C_(—) ₆alkenyl. O—C_)₆ alkynyl, hydroxyl, amino, or COOQ, C₂₋₆ alkenyl which isunsubstituted or substituted by or substituted by halogen nitro, CONH₂,COOH, O—C, alkyl, —C_alkenyl, —C_alkynyl hydroxyl, amino, or COOQ, C₂₋₆alkynyl which is unsubstituted or substituted by or substituted byhalogen, nitro, CONH, COOH O—C, alkyl O—C, alkenyl O—C_alkynyl, hydroxylamino, or COOQ, C₆₋₁₀ aryl which is unsubstituted or mono- ordi-substituted with OH, SH, amino, halogen or C₁₋₆ alkyl, or a hydroxyprotecting group; and Z is ORb, Rb is H, straight chain, branched chainor cyclic C₁₋₆ alkyl which is unsubstituted or substituted by orsubstituted by halogen, nitro, CONH₂, COOH, O—C_alkyl, O—C_alkenyl,O—C₁₋₆ alkynyl, hydroxyl, amino, or COOQ, C₂₋₆ alkenyl which isunsubstituted or substituted by or substituted by halogen, nitro, CONH,COOH, —C₁₋₆alkyl, O—C₂₋₆alkenyl, O—C₂₋₆ alkynyl hydroxyl, amino, orCOOQ, C₂₋₆ alkynyl which is unsubstituted or substituted by orsubstituted by halogen, nitro CONH₂, COOH, O—C_alkyl O—C_alkenylO—C_alkynyl hydroxyl amino, or COOQ, C₁₋₆ acyl, or a hydroxy protectinggroup; D₁ and D₂ are each independently N₃, F, or H, D₁ and D₂ can alsobe joined to be ═CH₂, ═CF₂, or C₃-cycloalkyl which is unsubstituted orsubstituted by or substituted by halogen, nitro, CONH₂, COOH, O—C₁₋₆alkyl, O—C₂₋₆ alkenyl, O—C₇₋₆ alkynyl, hydroxyl, amino, or COOQ; withthe proviso that when B is adenine, Z is ORb, D₁ is H, D₂ is H and Rb isH, Ra is not triphosphate or H, wherein said compound is notadministered in conjunction with an interferon.
 2. A method according toclaim 1 wherein Z is OH.
 3. A method according to claim 2 wherein D₁ isH and D₂ is F.
 4. A method according to claim 2 wherein Ra is H,monophosphate, diphosphate, or triphosphate.
 5. A method according toclaim 2 wherein Ra is triphosphate.
 6. A method according to claim 2wherein Ra is H.
 7. A method according to claim 3 wherein Ra is H,monophosphate, diphosphate, or triphosphate.
 8. A method according toclaim 3 wherein Ra is triphosphate.
 9. A method according to claim 3wherein Ra is H.
 10. A method according to claim 2 wherein B isadenin-9-yl, guanin-9-yl, inosin-9-yl, 2-amino-purin-9-yl,2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl,cytosin-1-yl, uracil-1-yl, 3-carboxamido-1,2,4-triazol-1-yl,3-deaza-adenin-9-yl, 3-deaza-guanin-9-yl, 3-deaza-inosin-9-yl,3-deaza-2-amino-purin-9-yl, 3-deaza-2-amino-6-chloro-purin-9-yl3-deaza-2-6-diamino-purin-9-yl, 7-deaza-adenin-9-yl,7-deaza-guanin-9-yl, 7-deaza-inosin-9-yl, 7-deaza-2-amino-purin-9-yl,7-deaza-2-amino-6-chloro-purin-9-yl, 7-deaza-2-6-diamino-purin-9-yl,7-deaza-8-aza-adenin-9-yl, 7-deaza-8-aza-guanin-9-yl,7-deaza-8-aza-inosin-9-yl, 7-deaza-8-aza-2-amino-purin-9-yl,7-deaza-8-aza-2-amino-6-chloro-purin-9-yl,7-deaza-8-aza-2-6-diamino-purin-9-yl, 8-aza-adenin-9-yl,8-aza-guanin-9-yl, 8-aza-inosin-9-yl, 8-aza-2-amino-purin-9-yl,8-aza-2-amino-6-chloro-purin-9-yl, 8-aza-2-6-diamino-purin-9-yl,5-aza-thymin-1-yl, 5-aza-cytosin-1-yl, 5-aza-uracil-1-yl,6-aza-thymin-1-yl, 6-aza-cytosin-1-yl, or 6-aza-uracil-1-yl; which ineach case is unsubstituted or substituted by at least one of NHR₃,C₁₋₆alkyl, —OC₁₋₆alkyl, Br, Cl, F, I or OH, wherein R₃ is H, C₁₋₆alkylor C₁₋₆acyl.
 11. A method according to claim 3 wherein B is chosen fromadenin-9-yl, guanin-9-yl, inosin-9-yl, 2-amino-purin-9-yl,2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl,cytosin-1-yl, uracil-1-yl, 3-carboxamido-1,2,4-triazol-1-yl,3-deaza-adenin-9-yl, 3-deaza-guanin-9-yl, 3-deaza-inosin-9-yl,3-deaza-2-amino-purin-9-yl, 3-deaza-2-amino-6-chloro-purin-9-yl3-deaza-2-6-diamino-purin-9-yl, 7-deaza-adenin-9-yl,7-deaza-guanin-9-yl, 7-deaza-inosin-9-yl, 7-deaza-2-amino-purin-9-yl,7-deaza-2-amino-6-chloro-purin-9-yl, 7-deaza-2-6-diamino-purin-9-yl,7-deaza-8-aza-adenin-9-yl, 7-deaza-8-aza-guanin-9-yl,7-deaza-8-aza-inosin-9-yl, 7-deaza-8-aza-2-amino-purin-9-yl,7-deaza-8-aza-2-amino-6-chloro-purin-9-yl,7-deaza-8-aza-2-6-diamino-purin-9-yl, 8-aza-adenin-9-yl,8-aza-guanin-9-yl, 8-aza-inosin-9-yl, 8-aza-2-amino-purin-9-yl,8-aza-2-amino-6-chloro-purin-9-yl, 8-aza-2-6-diamino-purin-9-yl,5-aza-thymin-1-yl, 5-aza-cytosin-1-yl, 5-aza-uracil-1-yl,6-aza-thymin-1-yl, 6-aza-cytosin-1-yl, or 6-aza-uracil-1-yl; which ineach case is unsubstituted or substituted by at least one of NHR₃,C₁₋₆alkyl, —OC₁₋₆alkyl, Br, Cl, F, I or OH, wherein R₃ is H, C₁₋₆alkylor C₁₋₆acyl.
 12. A method according to claim 2 wherein B is adenin-9-yl,guanin-9-yl, inosin-9-yl, 2-amino-purin-9-yl,2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl,cytosin-1-yl, 5-fluoro-cytosin-1-yl, uracil-1-yl, 5-fluorouracil or1,2,4-triazole-3-carboxamide base.
 13. A method according to claim 3wherein B is adenin-9-yl, guanin-9-yl, inosin-9-yl, 2-amino-purin-9-yl,2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl,cytosin-1-yl, 5-fluoro-cytosin-1-yl, uracil-1-yl, 5-fluorouracil or1,2,4-triazole-3-carboxamide base.
 14. A method according to claim 1wherein the compound of formula I is: 3′-deoxycytidine;3′-deoxycytidine-5′triphosphate; 5-Fluoro-3′-deoxycytidine;5-Fluoro-3′-deoxycytidine-5′triphosphate; 3′-deoxyuridine;3′-deoxyuridine-5′triphosphate; 5-Fluoro-3′-deoxyuridine;5-Fluoro-3′-deoxyuridine-5′triphosphate; 3′-deoxythymidine;3′-deoxythymidine-5′triphosphate; 3′-deoxyguanosine;3′-deoxyguanosine-5′triphosphate; 2-N-acetyl-3′-deoxyguanosine;2-N-acetyl-3′-deoxyguanosine-5′triphosphate; 5-Methyl-3′-deoxycytidine;5-Methyl-3′-deoxycytidine-5′triphosphate; 5-Iodo-3′-deoxycytidine;5-Iodo-3′-deoxycytidine-5′triphosphate; 5-Chloro-3′-deoxycytidine;5-Chloro-3′-deoxycytidine-5′triphosphate; 3′-fluoro-3′-deoxyguanosine;3′-fluoro-3′-deoxyguanosine-5′triphosphate; 3′-fluoro 3′-deoxycytidine;3′-fluoro 3′-deoxycytidine-5′triphosphate; 5-Iodo-3′-deoxycytidine;5-Iodo-3′-deoxycytidine-5′triphosphate; 5-Chloro-3′-deoxyuridine;5-Chloro-3′-deoxyuridine-5′triphosphate; 5-Bromo-3′-deoxyuridine;5-Bromo-3′-deoxyuridine-5′triphosphate; 6-Chloro-3′-deoxyguanosine;6-Chloro-3′-deoxyguanosine-5′triphosphate;3′-spirocyclopropyl-3′-deoxyguanosine;3′-spirocyclopropyl-3′-deoxyguanosine-5′triphosphate;3′-difluoro-spirocyclopropyl-3′-deoxyguanosine;3′-difluoro-spirocyclopropyl-3′-deoxyguanosine-5′triphosphate;3′-methylene-3′-deoxyguanosine;3′-methylene-3′-deoxyguanosine-5′triphosphate; 3′-difluromethylene3′-deoxyguanosine; 3′-difluromethylene 3′-deoxyguanosine-5′triphosphate;3′-spirocyclopropyl-3′-deoxycytidine;3′-spirocyclopropyl-3′-deoxycytidine-5′triphosphate;3′-difluoro-spirocyclopropyl-3′-deoxycytidine;3′-difluoro-spirocyclopropyl-3′-deoxycytidine-5′triphosphate;3′-methylene-3′-deoxycytidine;3′-methylene-3′-deoxycytidine-5′triphosphate; 3′-difluromethylene3′-deoxycytidine; 3′-difluromethylene 3′-deoxycytidine-5′triphosphate;9-β-D-xylofuranosyl-guanosine;9-β-D-xylofuranosyl-guanosine-5′triphosphate;9-β-D-xylofuranosyl-cytidine;9-β-D-xylofuranosyl-cytidine-5′triphosphate; 3′-azido-3′-deoxycytidine;3′-azido-3′-deoxycytidine 5′triphosphate; and or a pharmaceuticallyacceptable salts thereof.
 15. A method according to claim 1I whereinsaid compound is used in combination with at least one furthertherapeutic agent chosen from ribavirin, amantadine, rimantadine,interleukine-12, ursodeoxycholic acid (UDCA), glycyrrhizin and silybummarianum.
 16. A The method according to claim 2, wherein said compoundis used in combination with at least one further therapeutic agentchosen from ribavirin, amantadine, rimantadine, interleukine-12,ursodeoxycholic acid (UDCA), glycyrrhizin and silybum marianum.
 17. AThe method according to claim 3, wherein said compound is used incombination with at least one further therapeutic agent chosen fromribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholicacid (UDCA), glycyrrhizin and silybum marianum.
 18. A The methodaccording to claim 14, wherein said compound is used in combination withat least one further therapeutic agent chosen from ribavirin,amantadine, rimantadine, interleukine-12, ursodeoxycholic acid (UDCA),glycyrrhizin and silybum marianum.
 19. A method according to claim 1,wherein said method is a method of treatment.
 20. A method according toclaim 19, wherein Ra is H, monophosphate, diphosphate, triphosphate,carbonyl substituted by C₁₋₆ alkyl, C₂₋₆, C₂₋₆ alkynyl, or C₆₋₁₀ aryl or

Rc is, in each case independently, H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl or a hydroxy protecting group selected fromacetyl-2-thioethyl ester, pivaloyloxymethyl ester andisopropyloxycarbonyloxymethyl ester; and Rb is H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ acyl, or a hydroxy protecting group selectedfrom acetyl-2-thioethyl ester, pivaloyloxymethyl ester andisopropyloxycarbonyloxymethyl ester.
 21. A method according to claim 19,wherein B is adenin-9-yl, guanin-9-yl, inosin-9-yl, 2-amino-purin-9-yl,2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl,cytosin-1-yl, uracil-1-yl, or 3-carboxamido-1,2,4-triazol-1-yl, which ineach case is unsubstituted or substituted by at least one of NHR₃,C₁₋₆alkyl, —OC₁₋₆alkyl, Br, Cl, F, I or OH, wherein R₃ is H, C₁₋₆alkylor C₁₋₆acyl.
 22. A method according to claim 19, wherein B isadenin-9-yl, guanin-9-yl, 2-amino-purin-9-yl,2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl,cytosin-1-yl, uracil-1-yl, which in each case is unsubstituted orsubstituted by at least one of NHR₃, C₁₋₆alkyl, —OC₁₋₆alkyl, Br, Cl, F,I or OH, wherein R₃ is H, C₁₋₆alkyl or C₁₋₆acyl.
 23. A method accordingto claim 19, wherein B is guanin-9-yl, cytosin-1-yl, uracil-1-yl, whichin each case is unsubstituted or substituted by at least one of NHR₃,C₁₋₆alkyl, —OC₁₋₆alkyl, Br, Cl, F, I or OH, wherein R₃ is H, C₁₋₆alkylor C₁₋₆acyl.
 24. A method according to claim 19, wherein B isguanin-9-yl, cytosin-1-yl, 5′-fluoro-cytosin-1-yl, 5′-fluorouracil-1-ylor uracil-1-yl.
 25. A method according to claim 19, wherein B is

wherein X is H, halogen or NHR₁₀; R₁₀ is H, C₁₋₆acyl, C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl; Y is H, halogen or NHR₁₁; R₁₁ is H, C₁₋₆acyl,C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; Y₂ is H, halogen or NHR₁₂;R₁₂ is H, C₁₋₆acyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; R₉ is H,hydroxy protecting group, C₁₋₆acyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; Y₃ is H, halogen or NHR₁₃; R₁₃ is H, C₁₋₆acyl, C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl; R₇ is H, halogen, C₁₋₆acyl, C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl; and R₈ is H, halogen, C₁₋₆acyl, C₁₋₆ alkyl,C₂₋₆ alkenyl, or C₂₋₆ alkynyl.
 26. A method according to claim 25,wherein X is H, F, or NHR₁₀, R₁₀ is H, Y is H, F, or NHR₁, R₁₁ is H, Y₂is H, F, or NHR₁₂, R₁₂ is H, R₉ is H, Y₃ is H, F, or NHR₁₃R₁₃ is H, R₇is H, F, or C₁₋₆ alkyl, and R₈ is H, F, or C₁₋₆ alkyl.
 27. A methodaccording to claim 19, wherein Z is F or ORb, and ORb is H or methyl.28. A method according to claim 19, wherein D₁ and D₂ are N₃, F, or H inwhich D₁ and D₂ are not both H, or D₁ and D₂ together form cyclopropyl,difluorocyclopropyl-═CH₂, or ═CF₂.
 29. A method according to claim 19,wherein said compound is administered in an amount of 0.01 to about 750mg/kg of body weight per day.
 30. A method according to claim 19,wherein said compound is administered in unit dosages containing 10 to1500 mg of said compound per unit dosage.
 31. A method according toclaim 15, wherein said compound and said further therapeutic agent areeach administered as a formulation which further contains apharmaceutically acceptable carrier.
 32. A method according to claim 31,wherein said compound and said further therapeutic agent aresequentially administered, in separate or combined pharmaceuticalformulations.
 33. A method according to claim 31, wherein said compoundand said further therapeutic agent are simultaneously administered, inseparate or combined pharmaceutical formulations.
 34. A method accordingto claim 1, wherein said host is a human.
 35. A method according toclaim 19, wherein said host is a human.
 36. A method according to claim2, wherein said host is a human.
 37. A method according to claim 3,wherein said host is a human.
 38. A method according to claim 14,wherein said host is a human.